Number of children with grade 3 or 4 liver enzymes elevations compared to baseline, new onset of skin rash, nausea, vomiting or treatment modification due to drug side effects [ Time Frame: up to week 24 of therapy ] [ Designated as safety issue: Yes ]

Compare frequency of adverse events as a measure of safety and tolerability between HIV-infected children with and without TB coinfection

Number of children with efavirenz 24-hour post-dose concentration (C24h) < 1000 ng/mL [ Time Frame: At week 4 of therapy ] [ Designated as safety issue: No ]

Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6 516G>T, as well as CYP3A4, ABCB1, CAR and PXR polymorphisms) and efavirenz AUC0-24h and efavirenz C24h will be investigated

Number of children who discontinue efavirenz therapy due to drug side effects [ Time Frame: Up to week 24 of HIV therapy ] [ Designated as safety issue: Yes ]

Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6 polymorphisms) and treatment modification due to drug side effects in the combined study population

Efavirenz is an essential component of HIV treatment in children aged 3 years or older on anti-tuberculosis (anti-TB) treatment. However, the appropriate efavirenz dose during anti-TB treatment remains unclear. Rifampin (an anti-TB drug) increases the activity of the drug metabolizing enzymes that breakdown efavirenz, which may lead to low blood levels of efavirenz and treatment failure during cotreatment. The drug-to-drug interactions between the HIV and anti-TB drugs also vary between individuals based on genetic factors. This study will investigate the effects of anti-TB treatment, as well as drug-gene interactions on the blood concentrations of efavirenz in children with HIV and TB infections. Such data could enhance optimization of efavirenz dosage or selection of alternate regimens in some children.

Detailed Description

Efavirenz-based antiretroviral therapy (ART) is the preferred regimen in children older than 3 years on rifampin-containing anti-TB therapy. Efavirenz trough plasma concentrations below 1000 ng/mL have been associated with increased risk of virologic failure among HIV-infected adults, while concentrations above 4000 ng/mL have been associated with risk of central nervous system side effects. Efavirenz is primarily metabolized by hepatic CYP2B6, with secondary contributions from CYP2A6. On average, rifampin co-administration causes a 26% reduction in efavirenz plasma exposure but some individuals have paradoxically elevated efavirenz concentrations with co-administration in adult pharmacokinetic studies. The inter-individual variability in the drug-to-drug interactions suggest that efavirenz dose adjustment with concomitant anti-TB therapy may not be necessary in some patients. In children, there is very limited data on the pharmacokinetic interactions between rifampin-containing TB treatment and efavirenz. To our knowledge, there is only one published study in children to date. Among 15 TB/HIV co-infected children treated with standard efavirenz-based active antiretroviral therapy and rifampin-containing TB treatment, a wide inter-patient variability in efavirenz concentration as well as a bimodal distribution of efavirenz trough concentrations were observed. Overall, rifampin-containing anti-TB treatment had no significant influence on the mean change in efavirenz concentration in the study population as a whole, but 60% and 53% of children had efavirenz trough concentration < 1000 ng/mL during and after anti-TB, respectively. This data suggest that current dosing of efavirenz may be suboptimal in a large proportion of children irrespective of anti-TB therapy. To overcome the risk of under-dosing of efavirenz especially with concurrent anti-TB treatment, the WHO recommended prescribing the maximum dose for each weight-band when efavirenz is coadministered with anti-TB treatment. This study seeks to evaluate whether the current dosing of efavirenz provides adequate efavirenz concentrations in children, as well as explore how genetic factors influence efavirenz pharmacokinetics with concomitant anti-TB treatment. The specific hypotheses to be tested are:

At the population level, efavirenz plasma concentrations in TB/HIV co-infected children who are treated with the maximized weight-based efavirenz dosage during rifampin-containing anti-TB therapy will be comparable to concentrations in HIV-infected children receiving ART without anti-TB treatment.

Co-treatment with rifampin- and efavirenz-containing therapies will lead to substantially decreased (by at least 40%) efavirenz concentration in the children with CYP2B6 extensive but not in those with intermediate or slow metabolizer genotypes.

A two-arm, as well as a two-period pharmacokinetic study in HIV-infected children with and without TB will be performed at the Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana. Eligible participants will include children aged 3 - 14 years with HIV with or without TB coinfection, ART-naïve and eligible to initiate ART. The ART regimen will consist of the WHO recommended weight-band dosing of efavirenz (10-13.9kg - 200 mg; 14-24.9kg - 300mg; 25-39.9kg - 400 mg and > 40Kg - 600 mg), plus ZDV 180 - 240 mg/m2 and 3TC 4 mg/kg twice daily. Tenofovir may be used in place of ZDV. Standard anti-TB therapy will be prescribed to the co-infected patients and will start immediately upon TB diagnosis.

A complete medical history, physical examination, and staging of HIV disease will be performed before initiation of ART. Baseline measurements prior to initiation of ART will include CBC, blood urea nitrogen, creatinine, LFTs, CD4 cell count determination and plasma HIV-1 RNA level. Weeks 12 and 24 CD4 cell count and plasma HIV-1 RNA will obtained at scheduled follow-up. Pharmacokinetic sampling will be performed at week 4 of ART in both arms and at 4 weeks after anti-TB treatment in the co-infected group. At each sampling time, 3 mL of blood will be collected into an EDTA tube. Blood samples will be collected at times 0 2, 8, 12 and 24 hours post-dose for determination of efavirenz concentrations. Efavirenz concentrations in plasma will be measured using a HPLC-MS. After sample analysis, a data set will be constructed. Anticipated covariates included in this data set to be explored will include age, sex, weight, relevant drug-metabolizing enzyme genotype, TB therapy status (on/off), and CD4 cell count. Nonlinear mixed-effects modeling (using NONMEM, version VI) will be used to estimate pharmacokinetic parameters (CL/F, V/F, AUC, Cmin, Cmax, elimination rate constant), inter-individual error, and residual error. Results of this population analysis may be used to simulate alternative efavirenz dosing strategies in this TB/HIV co-infected population, or in relevant sub-populations with variant PK/pharmacogenetics.

Study Type ICMJE

Observational

Study Design ICMJE

Observational Model: CohortTime Perspective: Prospective

Target Follow-Up Duration

Not Provided

Biospecimen

Retention: Samples With DNA

Description:

EDTA plasma Whole blood DNA

Sampling Method

Non-Probability Sample

Study Population

HIV-infected children with and with TB aged 3 to 14 years old

Condition ICMJE

HIV

Tuberculosis

Intervention ICMJE

Not Provided

Study Group/Cohort (s)

Not Provided

Publications *

Not Provided

* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ICMJE

Recruiting

Estimated Enrollment ICMJE

160

Estimated Completion Date

May 2017

Estimated Primary Completion Date

May 2017 (final data collection date for primary outcome measure)

Eligibility Criteria ICMJE

Inclusion Criteria:

Children with active TB with or without HIV co-infection. Active TB diagnosis defined by clinical criteria consistent with active TB and/or a positive AFB smear or mycobacterial culture.

Aged 3 months to 14 years old

Are available for follow-up until completion of TB treatment and/or achievement of a study endpoint like discontinuation of therapy, and/or pharmacokinetic sampling.

Exclusion Criteria:

Unable to obtain informed signed consent parent(s) or legal guardian

Have AIDS-related opportunistic infections other than TB, history of or proven acute hepatitis within 30 days of study entry, persistent vomiting, or diarrhea